Concern is growing about the effects of environmental chemicals on human health. For example, published data show that bisphenol A (BPA), a xenoestrogen, circulates at nanogram per milliliter levels in the blood of pregnant women. Despite this fact, very little is known about its effects in terms of human development. Animal models, primarily mice and rats, suggest an array of untoward effects of BPA on the offspring that range from prostate and mammary gland abnormalities to neurodevelopmental disorders. Similarly, studies in animals suggest that this environmental chemical disrupts placentation, which results in impaired intrauterine growth. The latter finding is significant because a great deal of evidence suggests that many important parameters of adult health are programmed in utero. To date, the small amount of information that is known about BPA effects on the human placenta suggests there is ample cause for concern. Available data and our preliminary results show this environmental chemical acts in important parts of the pathways that govern its normal development and functions. Our group has studied human placentation for many years. We developed an in vitro model that supports differentiation of primary cytotrophoblasts (CTBs) isolated from early gestation placentas. This culture system has allowed us to study the role of important regulators of CTB differentiation including adhesion molecules, metalloproteinases, transcription factors, and immune molecules. Studying the normal process has revealed the pathological changes that contribute to pregnancy complications, such as preeclampsia, and the effects of xenobiotics that are associated with impaired growth, such as nicotine. Very recently we established a new in vitro system that allows us to model the critical early steps in formation of the human placenta. Specifically, we isolated human trophoblast progenitor cells (TBPCs) from early gestation placentas that form lines that continuously self-replicate in culture. Upon differentiation, the cells give rise to CTBs and syncytiotrophoblasts (STBs). Therefore, this model allows us to study fundamental aspects of human placental development that were previously inaccessible to experimentation. In this context, we hypothesize that BPA exposures in a range of concentrations that have been measured in maternal blood and placentas impair selective aspects of human placentation. To test this theory, we will study the effects of BPA on TBPC self-renewal (Aim 1) and differentiation to CTBs and STBs (Aim 2). We envision that the results of these experiments will provide important data regarding the consequences of BPA exposures on human placental development. These findings will enable future experiments to determine the in vivo relevance of these alterations by studying placental samples collected from women whose blood levels of BPA have been measured. PUBLIC HEALTH RELEVANCE: The effects of environmental chemicals on human health, especially endocrine disruptors, are an important area of investigation. In this context, the goal of this proposal is to study the effects of bisphenol A (BPA) exposures on human placentation. These experiments will employ a new cell culture model for studying human placental development, trophoblast progenitor cells (TBPCs). The approach is to determine BPA effects on TBPC self-renewal (Aim 1) and differentiation to cytotrophoblasts and syncytiotrophoblasts (Aim 2), which will enable identification of the major pathways that this environmental chemical disrupts.